Research Faculty

Address
1130 St. Nicholas Avenue
ICRC Room 505A
New York, NY 10032

Phone: 212-851-4779
Fax:

sz2296@columbia.edu
Education and Training
1998 M.D., Peking University, China.
2004 Ph.D., Johns Hopkins University
2009 Postdoc, Harvard University

Training Activities
Cancer Biology
Immunology
Shan Zha, M.D., Ph.D.
Assistant Professor of Pathology and Pediatrics
Research Summary

DNA damage occurs frequent in living cells. Breaks at the both strands of the DNA helix - DNA double strand breaks is the most severe form of DNA damage. It can happen during DNA replication, as a result of exposure to metabolic by products (e.g. reactive oxygen species) or environmental insults (e.g. radiation), or as programmed events required for lymphocyte development, specifically V(D)J recombination during the assembly of antigen receptor genes and Class Switch Recombination during B cell maturation. While those programmed DNA double strand break events are essential for the diversity and potency of adapted immune system, mistakes in resolving those programmed DNA double strand breaks often lead to large chromosome rearrangement such as translocation, gene amplification and deletions, which are the hallmarks of lymphoma and leukemia. As a result, human patients with mutations in DNA double strand break response and repair genes are often immune deficient and are predisposed to lymphoid malignancy.

Our lab is interested in understanding how mammalian cells sense DNA double stand breaks, integrate cell cycle progression and cellular survival to facilitate high-fidelity repair and to prevent oncogenic transformation. In particular we are interested in:

1) the functional interaction between ATM kinase and its downstream target proteins with non-homologous end joining pathway;
2) reveal the molecular mechanism of oncogenic translocations using ATM deficient mouse models;
3) understand the role of ATM autophosphorylation in DNA repair and tumor suppression;
4) understand the phosphorylation dependent regulation of DNA dependent protein kinase in DNA repair and tumor suppression.
5) develope and characterize mouse model for mantel cell lymphomas.
6) understand the role of non-homologous end-joining protein in hematopoietic stem cell function and in primary immunodeficiency.
7) understand the role of end-resection in oncogenic translocation

In the context, we have developed novel mouse models using gene-targeting, based on conditional inaction of ATM and other repair factors in different stage of developing lymphocytes. A broad range of laboratory approaches ranging from basic molecular genetic, biochemistry, cell biology to cytogenetic are applied to monitor the kinetics of DNA repair and consequence of repair deficiencies - translocations and oncogenic transformation.


Affilations

Institute for Cancer Genetics
Department of Pathology and Cell Biology
Department of Pediatrics
MD-PhD Program
Hematopathology
Herbert Irving Center
Integrated Program

Selected Publications

Yamamoto K, Wang Y, Jiang W, Dubois RL, Ludwig T, Lin C, Bakkenist CJ., Zha S. Kinase-Dead ATM protein causes genomic instability and early embryonic lethality in mice. Journal of Cell Biology 2012 Aug 6;198(3):305-13 PMID: 22869596

Liu X, Jiang W, Dubois RL, Yamamoto K, Wolner Z, Zha S. Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3903-8. PMID:22413262

Liu X, Zha S. ATMIN: A New Tumor Suppressor in Developing B Cells. Cancer Cell. 2011 May 17;19(5):569-70. Preview PMID: 21575856

Zha S, Jiang W, Fujiwara Y, Patel H, Goff PH, Brush JW, Dubois RL, Alt FW. Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2028-33.

Zha S, Guo C, Boboila C, Oksenych V, Cheng H, Zhang Y, Wesemann DR, Yuen G, Patel H, Goff PH, Dubois RL and Alt FW. XLF Has Functional Redundancy with ATM and H2AX in Non-homologous DNA End-joining. Nature 2011 Jan 13;469(7329):250-4.

Zha S, Bassing CH, Sanda T, Brush JW, Patel H, Goff PH, Gatti R, Look AT, Alt FW. ATM-Deficient Thymic Lymphoma Is Associated With Aberrant TCRδ Rearrangement And Gene Amplification. J Exp Med. 2010 Jul 5;207(7):1369-80.

Zha S, Boboila C, Alt FW. Mre11: roles in DNA repair beyond homologous recombination. Nat Struct Mol Biol. 2009 Aug;16(8):798-800 News and Views

Calle E, Jankovic M, Wong N, Zha S, Chen H, Difilippantonio S, Di Virgilio M, Heidkamp G, Alt FW, Nussenzweig A and Nussenzweig M. Essential Role for DNA-PKcs in DNA Double-Strand Break Repair and Apoptosis in ATM Deficient Lymphocytes. Mol Cell. 2009 May 15;34(3):285-97

Derudder M, Cadera EJ, Vahl JC, Wang J, Fox CJ, Zha S, van Loo G, Pasparakis M, Schlissel MS, Schmidt-Supprian M, Rajewsky K. Efficient κ-chain editing, but defective generation of λ+ B cells in the absence of NF-κB signaling. Nat. Immunology. Nat Immunol. 2009 Jun;10(6):647-54.

Li G, Alt FW, Cheng HL, Brush JW, Goff PH, Murphy MM, Franco S, Zhang Y, Zha S. Lymphocyte-Specific Compensation For XLF/Cernunnos End-Joining Functions In V(D)J Recombination. Mol. Cell. 2008 Sept.5;31(5):631-40.

Zha S, Sekiguchi J, Brush JW, Bassing CH, Alt FW. Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9302-6.

Zha S, Alt FW, Cheng HL, Brush JW, Li G. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4518-23.

Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA, Yan C, Tepsuporn S, Morales JC, Adams MM, Lou Z, Bassing CH, Manis JP, Chen J, Carpenter PB, Alt FW. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell. 2006 Jan 20;21(2):201-14.

Honors and Awards

2013-2018 Leukemia and Lymphoma Society Scholar
2013-2016 American Cancer Society Research Scholar Award
2012-2015 Gabrielle's Angel Foundation Medical Research Award
2010-2013 St. Baldrick Scholar for Pediatric Oncology
2010-2011 John M. Driscoll, Jr., M.D. Children's Fund Awards
2009 Bristol-Myers Squibb Oncology Award, American Association for Cancer Research
2007-2010 Senior Fellowship Award, Leukemia and Lymphoma Society
2004-2007 Fellowship Award, Leukemia and Lymphoma Society
2006 Young Investigator Award, Ataxia- Telangiectasia Workshop, Banff, Canada
2003 AFLAC Award, American Association for Cancer Research

Keywords

DNA repair, lymphocyte development, cancer and translocation


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